The objective of this project is to determine how early life exposures to persistent organic pollutants alter the skin microbiome, contribute to skin barrier defects and inflammation, and disrupt the establishment of immune tolerance to commensal microbes. The skin epidermal permeability barrier (EPB) forms late in development and is essential for life and health, preventing dehydration, and protecting against infection and physical and chemical insults. EPB dysfunction is a key feature of atopic dermatitis (AD; eczema), a common skin disorder characterized by chronic and relapsing, itchy, inflamed, skin lesions and dysbiotic microbiota. Recent dramatic increases in AD prevalence, especially in industrialized countries, suggest a strong environmental component to disease such as air pollution. We hypothesize that early in life exposures to environmental pollutants, such as 2,3,7,8-tetracholordibenzo-p-dioxin (TCDD) or diesel exhaust particles (DEP), that persistently activate aryl hydrocarbon receptor (AhR) signaling, affect the development of the skin microbiome, the EPB, and the establishment of immune tolerance to the commensal skin microbiome, leading to AD-like phenotypes of skin barrier dysfunction, inflammation and dysbiosis. We propose three aims to examine a critical neonatal development period where the newly formed EPB is exposed to the ex utero environment, assembles its microbiota, and establishes immunotolerance to this commensal microbiome.
In aim 1 we will determine the effect of AhR signaling and chemical exposures that activate AhR signaling on the assembly and function of the skin microbiome in concert with analyzing EPB function and inflammation.
In aim 2 we will test the role of the microbiome in regulating epidermal AhR signaling, and contribution to AD-like phenotypes in AhR exposure models.
In aim 3, we will investigate the role of AhR signaling in the establishment of tolerance to commensal microbes. Findings from the proposed studies should greatly enhance the understanding of how early life exposures to pollutants can disrupt the skin microbiome, its interactions with the host, and lead to skin disease.
Exposure to pollutants early in life can disrupt developmental processes and increase the risk of disease in newborns, children, and adults. The proposed studies will examine how early life exposures to pollutants that activate a cellular protein called the aryl hydrocarbon receptor may alter microbial colonization of the skin and the skin?s function as a barrier, thus increasing susceptibility to disease and infection. The findings will advance our understanding of how chemical exposures influence host-microbe interactions of the skin, while providing a foundation for novel therapeutic approaches for skin diseases such as atopic dermatitis.
